Cell-cell transfer and propagation of tau aggregates. Tauopathies are devastating neurodegenerative diseases. All are linked pathologically to misfolding and aggregation of the microtubule-associated protein tau, and include common disorders such as Alzheimer disease and frontotemporal dementia. Both wild-type tau protein and mutant forms associated with dominantly inherited diseases have the propensity to misfold and aggregate. In virtually all cases, disease begins in one brain region before spreading to involve other regions, and there is emerging evidence that this could be based on movement of protein aggregates between cells. This project seeks to understand the cellular mechanisms that govern tau aggregate uptake and release from cells, and how a tau aggregate taken into a cell manages to corrupt the endogenous, normally folded protein. The answers to these questions will provide immediate new opportunities for therapeutic strategies. The goals of this work are as follows: (1) Determine molecular mechanisms of tau uptake. We will use cell-based assays we have developed to study tau aggregate uptake, and to evaluate the molecular mechanisms that underlie this phenomenon. We will use mouse models to test predictions about pathways derived from our experiments in cell models. (2) Determine mechanisms of tau aggregate degradation and release. We believe that cellular pathways linked to protein degradation may play a role in processing tau protein aggregates, and might also be involved in allowing these aggregates to transfer between cells. We will test these ideas using a cellular model of aggregate transfer between cells. (3) Determine mechanisms of tau aggregate propagation. It is unclear how tau protein aggregates that move from one cell to another might lead to misfolding of protein in the recipient cell, and whether this movement can occur across synapses, as is suggested by new clinical studies. We will test whether tau protein aggregates corrupt protein on the cell interior through templated conformation change, whereby normally folded protein directly contacts aggregated forms. We will additionally test whether aggregates can move across synapses using a novel mouse model.